Analgetic compositions and methods



Nov, 8. 1966 HAJIME FUJIMURA ET AL 3,284,293

ANALGETIC COMPOSITIONS AND METHODS Filed Sept. 23, 1963 INVENTORS U) MM United States Patent 3,284,298 ANALGETIC COMPOSITIONS AND METHODS Hajime Fujimura, 9-2 Shishigatani-shimo-miyanomaecho, Sakyo-ku, Kyoto, Japan, and Kazuo Shinozald, 10 Izumi-cho, Nishinomiya, Hyogo, Japan Filed Sept. 23, 1963, Ser. No. 310,597 Claims priority, application Japan, Sept. 26, 1962, 37 42,261 12 Claims. (Cl. 161-65) This invention relates to novel analgetic compositions which are very effective and, in comparison with hithertoknown analgesics, are relatively free of side-effects. More specifically, the invention relates to pharmaceutical compositions which contain fl-hydroxybutyric acid p-phenetidide and ethoxybenzamide, and which may additionally contain vitamin B -active components, and/ or other pharmaceutically acceptable ingredients.

Many kinds of antipyretic analgesics are known and have been used for eliminating or mitigating human pain such as headache, toothache, menstrual pain and so on. They can in general be administered not only as simplex medicaments but, more often, as compositions thereof compounded with one or more other analgesics, hypnotics, sedatives, analeptics, etc. in expectation of strengthening or enhancing the analgetic effect and of diminishing side-effects. However, the known analgetic compositions are mostly prepared after so-called APC formulation-i.e. a combination of acetylsalicylic acid or aminopyrine, phenaoetin, and caffeine-and generally contain as a main ingredient either acetylsalicylic aicid or a pyrazclone-type medicament such as aminopyrine, sulpyrine (:sodium l-phenyl-2,3-dimethyl--pyrazolone-4-methylaminomethanesulfonate), pyrabital (=aminopyrine diethylbarbiturate, a compound of 2 moles of aminopyrine and 1 mole of barbital) or the like. It is well-known that acetylsalicylic acid or a pyrazolone-type medicament often causes drug eruption when administered to patients, especially those sensitive to said medicament. Moreover, especially in the case of a-cetylsalicylic acid, patients taking the medicament periodically even for a little while, are apt to suffer from gastric troubles. It has therefore long been a desideratum among medical men and pharmacologists to embody novel and excellent antipyretic analgesics other than of the so-called APC type.

The present invention, directed to the realization of this desideratum, is based upon an unexpectedly characteristic potentiation between ,B-hydroxybutyric acid p-phenetidide (hereinafter abbreviated as HEP) and ethoxybenzamide (hereinafter abbreviated as EB) in antipyretic and analgetic activities. Moreover, according to a further aspect of the invention, the characteristically potentiating efiect is further enhanced by the presence of vitamin B -active substances.

It is therefore a principal object of the present invention to provide novel and effective analgesic compositions which comprise as main ingredients at least HBP and EB, and which may further contain vitamin B -active substances and/ or ingredients and/ or so-called excipients. These novel compositions are characterized by the striking potentiation of effect among their ingredients and by the fact that there is no fear of producing pyrine eruption or acetylsalicylic acid eruption in the use of HBP and EB or the additional vitamin B -active substances.

HEP, one of the main ingredient of the composition, has the structure which is a phene-tidine derivative. This compound per se has excellent antipyretic and analgetic activities and is 3,284,298 Patented Nov. 8, 1966 of greatly reduced toxicity as compared with phenacetin (=acetophenetidine) as shown below:

(a) ACUTE TOXICITY TABLE 1 Animal Mice Rats Administration Oral, g./kg. Intraperi- Oral, gJkg.

toneal, gJkg.

HBP 4 .8 0.86 7.0 Phenacotiu 1.5 0.51 3 .7 N-acet yl-p-aminophenol D .68

(b) EFFECTIVITY The medicament to which the threshold amount of morphine hydrochloride (0.0025 g./kg.) has been added was administered intraperitoneally to mice, and analgetic activity was measured according to the Haifner method. From the results, the ED (=50% effective dose) was calculated according to the Litchfield-Wilcoxon method. The data are shown in Table 2, together with the respective calculated safety margins (=LD /ED TABLE 2 Compound EDso gjltg. Safety Margin HBP 0 .046 19.7 Phenacetin. 0 .066 8 .9 N-aeetyl-paininophenol c. 0 .10 6 .8

HEP per se can be orally administered to the human adult in. an amount of l.03.0 grams per day.

EB, i.e. ethoxybenzamide, is a salicylamide derivative having the structure:

and it has been confirmed that the analgetic activity of this compound is about 2.5 times as much as that of salicylarnide, and that, in comparison with salicylamide or acetylsalicylic acid, this BB is not only stronger and more lasting in antipyret ic activities but also has less sideefiects causing gastric troubles, inappetence, nausea, vomiting, tinnitus, dizziness, etc. Thus the LD of BB in the mouse or in the rat when administered orally is 1.51 g./kg. or 2.81 g./kg., respectively. The values show that the toxicity of BB is about half as compared with salicylamide, the LD of which is 0.95 g./kg. or 1.50 g./kg. in the mouse or rat, respectively, under the same conditions as in the case of EB. Usual dosage of EB per se is about 0.5-1.5 grams per day for the human adult.

The characteristic and strong potentiation between HBP and EB in analgetic activity upon which the present invention is based is confirmed, for example, as follows:

In the same way as described supra for HEP, after HBP and BB were concomitantly administered intrapenitoneally to mice together with the threshold amount (0.0025 g./kg.) of morphine hydrochloride, the resulting analgetic activity was measured according to the Haffner method. In this test, however, dosages of both HBP and BB were progressively varied so as to show 50% positive activity in the analgetic effect, yielding the result shown in the drawing. In the drawing the dotted line, which shows 50% positive activity of the analgetic effect by the simultaneous administration of HBP and EB, bends remarkably inwardly of the straight line drawn between the ED point of HBP on the ordinate and the EB point on the abscissa. (The ED value of HBP is 0.080 g./ kg. which somewhat differs from the value cited in Table 2, but this difference is merely due to the different season when the test was carnied out and on the strain of mice used in the test.)

The bending inwardly of the straight line shows the potentiation between HBP and EB in the analgetic effect, and .the greater bend, the stronger is the potentiating effect. On the contrary, if the dotted line would coincide with the straight line, the effect would only be additive; and if the dotted line would bend outwardly of the straight line, the effect would be antagonistic. (See I. H. Gaddurn: Pharmacology (fifth edition) published by Oxford University Press in 1959.)

Similar synergism is not observed in other combinations of related compounds, e.g. between HBP and aminopyrine, EB and aminopyrine, HBP and acetylsalicylic acid, EB and phenacetin, EB and N-acetyl-p-aminophenol, acetylsalicylic acid and phenacetin, acetylsalicylic acid wherein parenthesized figures show percentages relative to totals:

As shown in Table 4, when a composition consisting of HBP and EB is further compounded with a vitamin B -active substance, the analgetic effect of the former is remarkably strengthened. It is especially noteworthy that formulation A gave excellent effect in cases corresponding to 59.1 percent of those tested, while formulation B did so in 34.1 percent of the cases tested. Therefore, this invention is preferably carried out by compounding HBP, EB and at least one vitamin B -active substance. The vitamin B -active substances, used in the present invention, are exemplified by thiamine, diacetyl thiamine, dibenzoyl thiamine, thiamine propyl disulfide, thiamine p-hydroxyethyl disulfide, thiamine allyl disulfide, thiamine tetrahydrofurfuryl disulfide, thiamine disulfide, O-benzoylthiamine disulfide, S-benzoylthiamine O-monophosphate, 7-methoxycarbonyl-hept-Z-ene(1) thiamine disulfide, 3-acetylthio-7-methoxycarbonylheptyl thiamine disulfide or their pharmaceutically acceptable salts.

TABLE 4 Formulation A Formulation B Kind of pain Number of Excellent Effective Ineffec- Effective Number of Excellent Effective Inefifec- Effective cases (a (b) tive rate, cases (a (b) tive rate.

Medical Field:

Headache 71 29 (40.8) 35 (49.3) (9.9) (90.1) 56 (35.7) 30 (53.6) 6 (10.7) (89.3) Menstural pain... 151 81 (53.6) 47 (81.1) 2 (15.3) (84.7) 12 3 (41.7 3 (25.0 4 (33.3) (66.7) Neuralgia Myalgi 47 19 (40.4) 22 (46.8) (12.8) (87.2) 53 15 (28.3) 27 (50.9 11 (20.8) (79.2) Osteocope Arthralgia. 18 6 (33.3) 8 (44.4) (22.3) (77.7) 20 6 (30.0) 5 (25.0) 9 (45.0) (55.0)

Total 287 135 (47.0) 112 (30.0) 4 (14.0) (86.0) 141 46 (32.6) 65 (46.1) 30 (21.3) (78.7)

Dental Field:

Pains aitertooth extraction. 96 79 (82 3) (8.3) 9 (9.4) (90.6) 65 28 (43 1) 18 (27.7) 19 (29.2) (70.8) Pains after operation 44 33 (75.0) 7 (16.0) 4 (9.0) (91. 26 9 (34.6) 7 (26.9) 10 (35.3) (64.7) Toothache 81 53 (65.4) 16 (19.8) 12 (14.8) (85.2) 85 (29.4) 30 (35.3) 30 (35. (66.5)

Total 221 165 (74.7) 31 (14.0) 25 (11 3) (88.7) 176 62 (35.2) 55 (31.3) 59 (33.5) (66.5)

Total 508 300 (59.1) 143 (28.1) 65 (12 8) (87.2) 317 108 (34.1) 120 (37.9) 89 (28.0) (72.0)

and N-acetyl-p-aminophenol, salicylai'nide and HBP, The compositions of this invention may contain one salicylamide and phenacetin, etc. Nor has the potentiation as observed Ibetween HBP and EB been observed in any of the combinations mentioned above. Therefore, the potentiating effect between HBP and BB in analgetic activity is very specific to this combination among combinations between related compounds.

The same inclination between HBP and EB in analgetic activity was observed in tests in accordance with the Haffner method and the DAmour-Smith method. However, no interaction between HBP and EB in acute toxicity when both are administered concomitantly, is observed. Thus, in case of intraperitoneal administration to the mouse, the LD of HBP and EB are respectively 0.86 g./kg. and 0.50 g./kg., while the LD of an equiamount mixture of HBP and EB is 0.69 g./ kg. Therefore, notwithstanding the remarkable, and characteristic potentiation in analgetic activity, there is no interaction between HBP and BB in acute toxicity; this fact greatly enhances the utility of the concomitant administration of HBP and EB.

The strong analgetic activity of a mixture of HBP and EB is further fortified by the concomitant administration of a vitamin B -active substance. This can be proved, for example, by comparative clinical tests carried out in a variety of medical fields between formulation A and formulation B, the results being summarized in Table 4,

or more additional ingredients. These are exemplified by other analgesics such as acetylsalicylic acid, salicylamide, acetanilide, phenacetin, N-acetyl-p-aminophenol, antipyrine, aminopyrine, sulpyrine, isopropylantipyrine, aminopropylone, phenylbutazone, 1,4-diphenyl-3,5-dioxopyrazolidine, or the like; quinoline type derivatives such as quinine hydrochloride, quinine sulfate, quinine ethoxycarbonate, or the like; narcotic and non-narcotic potential analgesics such as codeine phosphate, dextro propoxyphene hydrochloride, or the like; analeptics such as caffeine, amphetamine, methamphetamine, or the like; sedatives such as bromural, phenobarbital, meprobamate, chlorpromazine, or the like; antihistaminics such as diphenhydramine salicylate, chlorpheniramine maleate, or the like; muscle relaxants such as mephenesin, chlorzoxazone, zoxazolamine, carisoprodol, phenylamidol, or the like; and antispasmodics or local anesthetics such as ethyl aininobenzoate, atropine sulfate, scopolia extract, or the h e.

Desirable amounts of the respective main ingredients to be compounded into the compositions of this invention vary with such factors as age, sex and symptoms of patients, but usually fall within the range of 0.05 to 3.0 grams of HBP and 0.05 to 3.0 grams of EB per day per 50 kilograms of body weight, and, if desired, a vitamin B -active substance as mentioned above is compounded in an amount more than 0.025 gram, but not exceeding 1.0 gram, desirably about 0.1 to 0.5 gram per da per 50 kilograms of body weight, with the composition of HBP and EB.

The compositions of the present invention may be administered to patients in the form of such pharmaceutical preparations as powders, granules, tablets, capsules, troches, drops, solutions, injections, emulsions, syrups, elixirs, etc. These preparations can be produced in accordance with per se known manner as those of usual pharmaceutical preparations.

As mentioned in the foregoing description, no potentiation was found between analgetic agents except in the combination of HBP and EB. In addition, the present invention provides a remarkable effect of vitamin B active substances on the analgetic agents or their compositions. In other words, when a vitamin B -active substance is compounded with analgetic compounds or analgetic compositions, according to the present invention, the analgetic activity of the analgesics is remarkably strengthened just as in the case of the composition comprising HBP and EB. Analgetic agents, the effect of which can be fortified with vitamin B -active substances, may be exemplified by aminobenzene derivatives such as acetanilide, phenacetin, N-acetyl-p-aminophenol, lactylphenetidine, HBP, cinnamoyloxyphenylurea, or the like; salicylic acid derivatives such as sodium salicylate, calcium salicylate, acetylsalicylic acid, calcium acetylsalicylate, aluminium acetylsalicylate, salicylosalicylic acid, salicylamide, EB, sodium gentisate, or the like; pyrazolone-type derivatives such as antipyrine, isopropylantipyrine, aminopyrine, sulpyrine, phenylbutazone, aminopropylone, 1,4- diphenyl-3,S-dioxopyrazolidine, or the like; quinoline derivatives such as quinine hydrochloride, quinine sulfate, quinine ethoxycarbonate or the like; their molecular compounds; their pharmaceutically acceptable salts; or a miX- ture of two or more kinds of them.

Recapitulating, the invention involves, in one aspect thereof, the mutual potentiation of HBP and EB with respect to their several analgetic activities, a result which has to be regarded as wholly unobvious, unforeseeable and unexpected in view of the absence of such potentiation in the hereinbefore-enumerated combinations of analgetics, and in a second aspect, the potentiation of analgetics generally as Well as in combinations thereof, including the special NBP/EB combination of the instant invention, by the concomitant administrationi.e. by the inclusion in the analgetic compositionof a vitamin B active substance.

The following examples of presently-preferred typical embodiments of the invention are only for illustration of the latter and are not at all intended to limit or restrict the scope of this invention.

Example 1 (Tablets) formulation: Per table, mg. HBP 150 EB 150 Dibenzoyl thiamine 25 Caffeine 25 Corn starch 79 Sodium laurylsulfate 2 Ethylcellulose 5 Magnesium stearate 4 HBP, EB, di=benzoyl thiamine, caffeine, the major part of the corn starch as such, sodium laurylsu'lfate and eflhylcellulose are admixed, and the remainder of the corn starch as %-corn starch paste (aqueous) is added to the mixture. Well kneaded, the mixture is disintegrated and dried in air stream. The dried granules are sprinkled with magnesium stearate and the mixture is punched to make tablets.

These tablets constitute excellent analgetic dosage unit compositions.

In this example, the caffeine may be replaced by 1.25 milligrams of dextro amphetamine sulfate to give essentially the same result.

Example 2 (Granules) formulations: Parts by weight HBP 300 E13 300 Dibenzoyl thiamine 50 Caffeine 50 Corn starch 296 Sodium laurylsulfate 4 All ingredients except a part of corn starch are thoroughly admixed, after which the mixture is kneaded with the remainder of the corn starch in the form of a 10% aqueous paste, followed by granulating and drying in air stream to produce granules, which may be administered in dosage unit form as an ana'lgetic.

Example 3 (Capsules) formulation: Per capsule, mg. HBP EP 150 Dibenzoyl thiamine 25 Caffeine 25 Lactose 48 Sodium laurylsulfate 2 All ingredients are thoroughly admixed and the mixture is packed in gelatine capsules. Each capsule constitutes an excellent an-algetically effective single dosage unit.

In this example, the caffeine may be replaced by 1.25 milligrams of methamphetamine hydrochloride to give essentially the same results.

As is manifest from the foregoing examples, the preferred compositions of the invention contain the HBP, the EB, the vitamin B -active substance and caifeine (as an optional additive) in a 6 :6:1:1 ratio by weight, optimum results being thus obtained (cf. also Table 3).

As to details and procedures of Litchfield-Wilcoxon method, Haifner method and DAmou r-Smith method, which are cited hereinibefore, the following references will be helpful for readers understanding:

(1) Litchfield-Wilcoxon method: The Journal of Ptharmacology and Experimental Therapeutics, volume 96, page 99 (1949);

(2) Haffner method: Deutsche Medizinische Wochenschrift, volume 55, page 731 (1929);

(3) DAmour-Smith method: The Journal of Pharmacology and Experimental Thenapeutics, volume 72, page 74 (1941).

Having thus disclosed the invention what is claimed is:

1. An analget'ic composition, which comprises, as active ingredients, from 0.05 to 3.0 grams of fi-h'ydroxybutyric acid p-phenetidide per 0.05 to 3.0 grams of ethoxybenzamide, together with pharm-aceut-ically acceptable carrier therefor.

2. An analgetic com-position, which comprises from 0.05 to 3.0 grams of fi-hydroxybutyric acid p-pthenet'idide per 0.05 to 3.0 grams of ethoxybenzamide and per 0.025 to 1.0 gram of a vitamin B -active substance, together with a pharmaceutically acceptable carrier therefor.

3. An analgetic composition, which comprises from 0.05 to 3.0 grams of ,B-hydroxybutyric acid p-phenetidide per 0.05 to 3.0 grams of ethoxybenzamide and per 0,025 to 1.0 gram of a vitamin B -active substance and a minor amount, relative to said first two ingredients, of a member selected from flhe group consisting of caffeine, am.-

phetamine and methamphetamine, together with pharmace-utically acceptable carrier therefor.

4. A composition as claimed in claim 2, wherein the vitamin B -active substance is dibenzoyl thiamine.

5. A composition as claimed in claim 3, wherein the vitamin B -active substance is dibenzoyl thiamine.

6. An analgetic composition, which comprises fi-hydroxybutyric acid p-phenetidide, ethoxybenzamide, a vitamin B -active substance and caffeine in the ratio of 6:6: 1:1 on weight basis, together with a pharmaceutieally acceptable carrier therefor.

7. An anal-getic composition which comprises B-hydroxybutyric acid p-phenetidide, ethoxybenzamide, a vitamin B active substance, and a member selected from the group consisting of amphetamine and methamphetamine in the ratio of 120:120:20:1 on Weight basis, together with a pharmaccutically acceptable carrier therefor.

8. A composition as claimed in claim 6, wherein the vitamin B active substance is dibenzoyl thiamine.

9. A composition as claimed in claim 7, wherein the vitamin B -active substance is dibenzoyl thiamine.

10. The method of combating pain which comprises administering to a human or animal requiring relief from pain an analgetic composition, which comprises, as active ingredients, from 0.05 to 3.0 grams of fi-hydroxybutyric :acid p-phenetidide per 0.05 to 3.0 grams of ethoxybenzamide, per day per 50 kilograms of body weight.

11. The method of combating pain which comprises administering to a human or animal requiring relief from pain an analgetic composition, with comprises from 0.05 to 3.0 grams of fi-hydroxybutyric acid p-phenetidide per 0.05 to 3.0 grams of ethoxybenz'amide and per 0.025 to 1.0 gram of a vitamin B -active substance, per day per kilograms of body weight.

12. The method of combating pain which comprises administering to a human or animal requiring relief from pain an analgetic composition, which comprises from 0.05 to 3.0 grams of B-hydroxybutyric acid p-phenetidide per 0.05 to 3.0 grams of ethoxybenZami-de and per 0.025 to 1.0 gram of a vitamin B active substance and a minor amount, relative to said first two ingredients, of a member selected from the group consisting of caffeine, amphetamine and methamphetamine, per day per 50 kilograms of body weight.

References Cited by the Examiner UNITED STATES PATENTS 4/1958 Ehrha-rt et a1 260-562 OTHER REFERENCES JULIAN E. LEVITT, Primary Examiner.

M. J. COHEN, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,284,298 November 8, 1966 Hajime Fujimura et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

In the heading to the printed specification, lines 3 4 and 5, for "Hajime Fujimura, 9-.2 Shishigatanishimomiyanomae Sakyoku,Kyoto, Japan, and Kazuo Shinozaki, 10 Izumi-cho, Nishinomiya, Hyogo, Japan" read Hajime Fujimura, Kyoto, Japan, and Kazuo Shinozaki, Hyogo, Japan, assignorsto Takeda Chemical Industries, Ltd. Higashiku, Osaka, Japan Signed and sealed this 12th day of September 1967.

(SEAL) Atteet;

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

10. THE METHOD OF COMBATING PAIN WHICH COMPRISES ADMINISTERING TO A HUMAN OR ANIMAL REQUIRING RELIEF FROM PAIN AN ANALGETIC COMPOSITION, WHICH COMPRISES, AS ACTIVE INGREDIENTS, FROM 0.05 TO 3.0 GRAMS OF B-HYDROXYBUTYRIC ACID P-PHENETIDIDE PER 0.05 TO 3.0 GRAMS OF ETHOXYBENZAMIDE, PER DAY PER 50 KILOGRAMS OF BODY WEIGHT. 